Progress in Neuro-Psychopharmacology & Biological Psychiatry 63 (2015) 1422

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Progress in Neuro-Psychopharmacology & Biological

Psychiatry
journal homepage: www.elsevier.com/locate/pnp

Deviant white matter structure in adults with

attention-decit/hyperactivity disorder points to aberrant myelination
and affects neuropsychological performance
A. Marten H. Onnink a,c, Marcel P. Zwiers b, Martine Hoogman c, Jeanette C. Mostert b,c, Janneke Dammers a,c,
Cornelis C. Kan a, Alejandro Arias Vasquez a,c,d, Aart H. Schene a, Jan Buitelaar d,e, Barbara Franke a,c,
a

Department of Psychiatry, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, The Netherlands
Donders Institute for Brain, Cognition and Behaviour, Centre for Cognitive Neuroimaging, Radboud University Nijmegen, Nijmegen, The Netherlands
c
Department of Human Genetics, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, The Netherlands
d
Department of Cognitive Neurosciences, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, The Netherlands
e
Karakter Child and Adolescent Psychiatric University Centre, Nijmegen, The Netherlands
b

a r t i c l e

i n f o

Article history:
Received 9 February 2015
Received in revised form 27 April 2015
Accepted 27 April 2015
Available online 5 May 2015
Keywords:
Adult ADHD
Cognitive performance
Corpus callosum
DTI
Radial diffusivity
Symptom severity

a b s t r a c t
Attention-decit/hyperactivity disorder (ADHD) in childhood is characterized by gray and white matter abnormalities in several brain areas. Considerably less is known about white matter microstructure in adults with
ADHD and its relation with clinical symptoms and cognitive performance. In 107 adult ADHD patients and 109
gender-, age- and IQ-matched controls, we used diffusion tensor imaging (DTI) with tract-based spatial statistics
(TBSS) to investigate whole-skeleton changes of fractional anisotropy (FA) and mean, axial, and radial diffusivity
(MD, AD, RD). Additionally, we studied the relation of FA and MD values with symptom severity and cognitive
performance on tasks measuring working memory, attention, inhibition, and delay discounting. In comparison
to controls, participants with ADHD showed reduced FA in corpus callosum, bilateral corona radiata, and thalamic
radiation. Higher MD and RD were found in overlapping and even more widespread areas in both hemispheres,
also encompassing internal and external capsule, sagittal stratum, fornix, and superior lateral fasciculus. Values of
FA and MD were not associated with symptom severity. However, within some white matter clusters that distinguished patients from controls, worse inhibition performance was associated with reduced FA and more impulsive decision making was associated with increased MD. This study shows widespread differences in white
matter integrity between adults with persistent ADHD and healthy individuals. Changes in RD suggest aberrant
myelination as a pathophysiological factor in persistent ADHD. The microstructural differences in adult ADHD
may contribute to poor inhibition and greater impulsivity but appear to be independent of disease severity.
2015 The Authors. Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND license
(http://creativecommons.org/licenses/by-nc-nd/4.0/).

1. Introduction
Attention-decit/hyperactivity disorder (ADHD) is a common childhood psychiatric disorder with an estimated prevalence around 5.3% in
childhood that persists through adolescence reaching a prevalence of up
to 4.9% in adults (Simon et al., 2009). ADHD is associated with global
and regional brain volume reductions. Meta-analytic ndings show reductions in total cerebral volume, in frontal lobes, cingulate cortex,
Abbreviations: ADHD, Attention-decit/hyperactivity disorder; DTI, Diffusion tensor
imaging; TBSS, Tract-based spatial statistics; FA, Fractional anisotropy; MD, Mean
diffusivity; AD, Axial diffusivity; RD, Radial diffusivity; ROI, Region of interest; SAD,
Sustained attention dots; SART, Sustained attention to response task.
Corresponding author at: Radboud University Medical Center, Department of Human
Genetics (855), PO Box 9101, 6500 HB Nijmegen, The Netherlands. Tel.: +31 24 3614017.
E-mail address: barbara.franke@radboudumc.nl (B. Franke).

and corpus callosum; in addition, robust evidence exists for decreased

gray matter volume in subcortical areas (Ellison-Wright et al., 2008;
Frodl and Skokauskas, 2012; Nakao et al., 2011; Valera et al., 2007). Differences in subcortical structures such as the putamen and caudate
seem to disappear with increasing age (Castellanos et al., 2002; Nakao
et al., 2011). Moreover, longitudinal studies show a delay in the age
by which peak cortical thickness is reached in ADHD patients (Shaw
et al., 2007), which has led to the suggesting that ADHD may be the outcome of a maturational lag that eventually normalizes (Rubia, 2007).
More recent results of longitudinal studies indicate, however, that reductions in basal ganglia, which were detected in childhood, persisted
into adolescence (Shaw et al., 2014). Cross-sectional studies in adults
with ADHD also point to persistent gray matter reductions in subcortical
volumes (Frodl et al., 2010; Onnink et al., 2014; Proal et al., 2011;
Seidman et al., 2011) as well as in cortical areas (Ahrendts et al., 2011;

http://dx.doi.org/10.1016/j.pnpbp.2015.04.008
0278-5846/ 2015 The Authors. Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

A.M.H. Onnink et al. / Progress in Neuro-Psychopharmacology & Biological Psychiatry 63 (2015) 1422

Amico et al., 2011; Biederman et al., 2008; Makris et al., 2007; Seidman
et al., 2006, 2011), and in cerebellar regions (Proal et al., 2011; Seidman
et al., 2011).
Over the last decade, the focus of neuroimaging research has widened
from studies of regional volume alterations to studies of altered white
matter connections within and among several neural networks (Konrad
and Eickhoff, 2010). Advances in diffusion tensor imaging (DTI) allowed
non-invasive investigation of white matter tracts connecting cortical
and subcortical regions (Thomason and Thompson, 2011). DTI probes
both the microstructural organization and the myelination of white
matter through measuring the diffusion of water molecules in the tissue
(Beaulieu, 2002; Le Bihan et al., 2001). Commonly used parameters are
fractional anisotropy (FA) and mean diffusivity (MD), which reect the
preferential directionality of water diffusion along white matter tracts
and the magnitude of diffusion, respectively (Le Bihan et al., 2001).
Although decreased FA is a characteristic of impaired white matter integrity, its exact neurobiological meaning is not fully understood (Beaulieu,
2002).
Impaired white matter integrity has been found in numerous psychiatric disorders including major depressive disorder (Korgaonkar
et al., 2011), bipolar disorder (Barysheva et al., 2013), schizophrenia
(Mandl et al., 2013) and ADHD. A meta-analysis in children, adolescents,
and adults with ADHD provided evidence of microstructural abnormalities in areas such as the anterior corona radiata (ACR), forceps minor,
bilateral internal capsule, and cerebellum (van Ewijk et al., 2012). This
meta-analysis only included hypothesis-free whole-brain voxelwise
(VBA) approaches and could not provide directionality of ndings
(e.g., higher or lower FA in ADHD). Hypothesis-driven region of interest
(ROI) studies reported that ADHD is in general associated with lower
FA in the corpus callosum (Cao et al., 2010), cerebellum (Bechtel et al.,
2009), and in several fronto-striatal tracts (Hamilton et al., 2008;
Pavuluri et al., 2009; Shang et al., 2013; Wu et al., 2014). Some studies
revealed that ADHD patients had higher FA (de Zeeuw et al., 2012; Silk
et al., 2009; Tamm et al., 2012) in fronto-striatal regions when compared with healthy controls. A recent study found clusters of decreased
FA and MD in most of the major white matter tracts and concluded that
white matter alterations are a wide-ranging rather than localized feature in children and adolescents with ADHD (van Ewijk et al., 2014).
Analyses using graph theory in combination with whole-brain DTI
(e.g., brain connectomics) revealed similarly that, in children and adolescents with ADHD, decreased white matter connectivity in frontostriatal circuits extended to a larger brain network which encompassed
additional cortico-cortical, subcortical, and cerebellar circuits (Hong
et al., 2014). The few available DTI studies of adult ADHD patients to
date showed decreased FA in tracts such as the cingulum bundle
(Makris et al., 2008), the inferior longitudinal fasciculus (ILF) (Konrad
et al., 2012), the superior longitudinal fasciculus (SLF) (Cortese et al.,
2013; Makris et al., 2008), and the corpus callosum (Dramsdahl et al.,
2012). Although the current ADHD literature lacks longitudinal DTI
studies, decreased FA has been reported in persistent and remitted
adult patients with ADHD in comparison with healthy controls. These
persistent ndings were observed in areas including the corona
radiata, sagittal stratum, the retrolenticular internal capsule, and the
SLF (Cortese et al., 2013). Conversely, another study found that remitted
adult patients did not differ signicantly from controls, while patients
with persistent ADHD had decreased FA in the uncinated and inferior
fronto-occipital fasciculi (Shaw et al., 2015).
Decreased FA is typically accompanied by increased MD values
in studies of ADHD. Increased MD is related with decreased cellular density (Alexander et al., 2007) and may reect abnormalities in ADHD
more sensitively than FA (de Luis-Garcia et al., 2015; Lawrence et al.,
2013). Moreover, decreased FA might result from increased radial diffusivity (RD) and/or reduced axial diffusivity (AD) (Alexander et al.,
2007). While the biological correlates of those measures are not yet
entirely claried, decreases in AD are currently thought to indicate axonal damage or degeneration, and increases in RD with minimal changes

15

in AD are thought to indicate increased freedom of cross-bre diffusion

and possibly decreased myelination (Alexander et al., 2007; Song et al.,
2002). Reporting changes in RD and AD could potentially help elucidate
the FA ndings in studies of ADHD. In the ADHD childhood literature, reports on RD have shown the entire range from increased RD (Helpern
et al., 2011; Nagel et al., 2011) to decreased RD (Silk et al., 2009), and
one study reported no change in RD (Tamm et al., 2012). Increased AD
(together with an increased FA) has been reported in two childhood
studies (Silk et al., 2009; Tamm et al., 2012). A recent study in adult
ADHD patients suggested that reductions of FA were driven by changes
in RD rather than AD (Shaw et al., 2015).
In addition to casecontrol comparisons, some studies investigated
the behavioural implications of changed white matter variation in
patients with ADHD by looking at its association with clinical symptoms
or cognitive measures. Although ndings in the ADHD literature are heterogeneous and complex, most studies have found that increasing
symptom severity was associated with decreased FA (Ashtari et al.,
2005; Nagel et al., 2011; Shang et al., 2013), but also with higher FA
(Peterson et al., 2011; van Ewijk et al., 2014). In an adult ADHD study,
attentional performance correlated with FA and MD in the right SLF,
and measures of impulsivity correlated with FA in right orbitofrontal
bre tracts (Konrad et al., 2010).
Taken together, there is strong evidence for wide-spread white
matter differences in ADHD patients compared to controls, and these
may be related to ADHD symptomatology and cognitive functioning.
Findings in the ADHD literature differ in precise location and directionality, which makes comparison of studies difcult. This is likely due to
differences in sample characteristics (e.g., gender, age ranges), small
sample sizes, and methodological differences (e.g., use of VBA versus
ROI approaches). Relative to childhood and adolescent ADHD studies,
there are few DTI studies in adult patients, and those are hampered
by small sample sizes and by the use of ROIs instead of whole-brain
approaches (except for the study by Cortese et al. (2013)). In adult
ADHD, only few studies investigated AD and RD (Shaw et al., 2015),
associations with ADHD symptomatology (Dramsdahl et al., 2012;
Shaw et al., 2015), and cognitive performance (Konrad et al., 2012).
Therefore, an overall picture of white matter pathology in adult ADHD
is currently lacking.
In this study, we used DTI to comprehensively compare white matter variation in adults with ADHD and healthy controls. We investigated
values of FA, MD, AD, and RD using tract-based spatial statistics (TBSS),
which is a whole-skeleton voxel-by-voxel analysis (Smith et al., 2006).
Within the ADHD group, we investigated associations of FA and MD
with clinical symptom scores and cognitive measures. These cognitive
measures were selected to cover prominent cognitive domains commonly affected in adults with ADHD (e.g., working memory, attention,
inhibition, and delay discounting/impulsivity). Based on the current
literature, we expected to nd (a) widespread decreases of FA and
increases of MD and RD in ADHD, and (b) associations of FA with symptom severity and cognitive performance.
2. Materials and methods
2.1. Subjects and procedure
In total, 216 individuals (107 patients with persistent ADHD, 109
healthy controls) from the Dutch cohort of the International Multicentre
persistent ADHD CollaboraTion (IMpACT) (Franke et al., 2010) participated in this study. The patients and an age-, gender-, and IQ-matched
group of healthy controls were recruited through the Department of
Psychiatry of the Radboud University Medical Center and through
advertisements.
Patients were included if they met DSM-IV-TR criteria for ADHD in
childhood as well as adulthood, as assessed by a psychiatrist. At the
time of inclusion into the study, participants were assessed using the
Diagnostic Interview for Adult ADHD (DIVA) (Kooij, 2010). This

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A.M.H. Onnink et al. / Progress in Neuro-Psychopharmacology & Biological Psychiatry 63 (2015) 1422

Table 1
Demographic, clinical, and cognitive characteristics of ADHD patients and healthy controls (HC).

Gender (males/females)
Age (years)
IQa
Inattention symptomsb
Hyperactivity/impulsivity symptomsb
Digit spanc
SADd
SARTe
Delay discountingf
DTI acquisition protocolg
One or more depressive episode(s) (remitted)h
Anxiety disorder (remitted)h
Substance use disorder (remitted)h
Borderline Personality Dh
Medication-naive
On stimulant medication
Medication in the past
On atomoxetine

ADHD
(N = 107)

HC
(N = 109)

Test of signicance

41/66
35.00 10.30
108.13 14.43
7.27 1.56
5.65 2.36
6.77 2.2
3.53 0.26
11.02 4.76
0.038 0.064
35 (33%)
52 (57%)
22 (23%)
21 (20%)
10 (9%)
20 (19%)
64 (60%)
14 (13%)
9 (8%)

47/62
36.08 10.97
110.97 15.36
0.59 1.29
0.59 1.12
7.53 2.38
3.42 0.19
9.29 5.04
0.010 0.015
23 (21%)
12 (11%)
6 (6%)
6 (6%)

2 = 0.51, p = .47
t (1,214) = 0.74, p = .46
t (1,214) = 1.40, p = .16
t (1,214) = 34.48, p b .0001
t (1,214) = 19.96, p b .0001
F(1,208) = 6.56, p b .01
F(1,202) = 11.94, p b .001
F(1,187) = 5.31, p = .02
F(1,187) = 16.31, p b .0001
2 = 3.71, p = .05

Demographic information representing means standard deviations or percentage per group.

a
Prorated from Block Design and Vocabulary of WAIS-III-R.
b
As measured with the ADHD-DSM-IV Self Rating scale (Kooij et al., 2005).
c
Digit Span raw backwards score (working memory).
d
Errors Sustained Attention Dots (SAD) task (attention).
e
Commission errors Sustained Attention to Response Task (SART) (inhibition).
f
Score on Delay Discounting task (impulsivity).
g
First version of DTI acquisition protocol.
h
As measured by the Structured Clinical Interview for DSM-IV for axis I (Groenestijn et al., 1999) and axis II (Weertman et al., 2000) disorders.

interview focuses on the 18 DSM symptoms of ADHD and uses concrete

and realistic examples to thoroughly investigate, whether a symptom is
currently present or was present in childhood. In order to obtain
information about ADHD symptoms and impairment in childhood,
additional information was acquired from parent and school reports,
whenever possible. The Structured Clinical Interview for DSM-IV
(SCID-I & SCID-II) was used for comorbidity assessment (see Table 1).
Assessments were carried out by trained professionals (psychiatrists
or psychologists). In addition, a quantitative measure of clinical symptoms was obtained using the ADHD-DSM-IV Self Rating scale (Kooij
et al., 2005).
Exclusion criteria for participants were psychosis, alcohol or substance
use disorder in the last 6 months, current major depression, full-scale IQ
estimate b70 (assessed using the Wechsler Adult Intelligence Scale-III),
neurological disorders, sensorimotor disabilities, non-Caucasian ethnicity,
and medication use other than psychostimulants, atomoxetine, or
bupropion. An additional exclusion criterion for the healthy control subjects was a current neurological or psychiatric disorder according to
SCID-I and SCID-II. This study was approved by the regional ethics
committee (Centrale Commissie Mensgebonden Onderzoek: CMO Regio
ArnhemNijmegen; Protocol number III.04.0403). Written informed
consent was obtained from all participants.
2.2. Acquisition of diffusion-weighted images
Whole-brain imaging was performed with a 1.5 Tesla MR scanner
(Magnetom Avanto, Siemens Medical Systems, Erlangen, Germany)
and a standard 8 channel head coil. A 3D T1-weighted MPRAGE anatomical scan was obtained from each subject (Repetition Time (TR) =
2730 ms, Echo Time (TE) = 2.95 ms, Inversion Time (TI) = 1000 ms,
ip angle = 7, eld of view = 256 256 176 mm3, voxel size =
1.0 1.0 1.0 mm3). The T1 images served as high resolution anatomical reference image for diffusion imaging data. Transversely oriented
diffusion-weighted images were acquired using a twice-refocused
spin-echo-planar-imaging sequence that minimized imaging distortions from eddy currents (Reese et al., 2003). The diffusion imaging
data were acquired using two different protocols. Fifty-eight subjects

were scanned with the following protocol: TR = 10200 ms, TE =

95 ms, eld of view = 320 320 160 mm3, voxel size = 2.5
2.5 2.5 mm3, 6/8 partial Fourier. Four images without diffusionweighting (b = 0 s/mm2) and 30 images with diffusion-weighting
(b = 900 s/mm2, diffusion directions = 34) applied along noncollinear directions were acquired. The remaining 158 subjects were
scanned with an improved second protocol, which was implemented
to reduce motion artifacts during scanning. Parameters that differed
from the rst protocol were TR (6700 ms), TE (85 ms), eld of view
(220 220 140 mm3), and scans were acquired with full Fourier
acquisition, other parameters were unchanged. For each slice, the
diffusion-weighting for the 30 images changed to b = 900 s/mm2.
Acquisition protocol was included as covariate in all analyses.

2.3. Preprocessing and skeletonization of diffusion-weighted images

The diffusion-weighted data was preprocessed using an in-house
developed algorithm. In short, the diffusion-weighted images of each
subject were realigned on the unweighted image using mutual information routines from SPM8 (Wellcome Trust Center for Neuroimaging).
Next, an iteratively reweighted-least-squares algorithm (PATCH) was
used to robustly correct for head and cardiac motion artifacts in the
diffusion-weighted data (Zwiers, 2010). Using DTIFIT from the FMRIB's
Diffusion Toolbox (part of FMRIB's Software Library (FSL)), FA images
were created and subsequently fed into the TBSS pipeline (Smith
et al., 2006). Here, all individual FA maps were nonlinearly registered
to the FMRIB58_FA template using FSL's nonlinear registration tool
FNIRT. Then, the nonlinear transforms found in the previous stage
were applied to all subjects to bring them into standard Montreal Neurological Institute (MNI) space. A mean FA image was created and
thinned to create a mean FA skeleton which represents the centres of
all tracts common to the group. A threshold of 0.2 was used to avoid partial voluming effects. Individual FA images were then mapped onto this
skeleton resulting in a skeletonized FA image for each individual. Finally,
each participant's FA, MD, AD, and RD image was projected onto this
skeleton, and resulting data were used for voxel-wise statistics.

A.M.H. Onnink et al. / Progress in Neuro-Psychopharmacology & Biological Psychiatry 63 (2015) 1422

2.4. Neuropsychological assessment

Cognitive functioning of participants was assessed by a neuropsychological test battery that was composed to cover multiple
cognitive domains earlier found affected in ADHD (Mostert et al.,
submitted for publication): (i) working memory, assessed via the
WAIS-III Digit Span task (Wechsler, 1997); (ii) attention, measured
with the response bias variable of the Sustained Attention Dots task
(De Sonneville, 1999); (iii) inhibition, tested via the Sustained Attention to Response Task (SART) (Smit et al., 2004); and (iv)
delay discounting/impulsivity assessed via the Delay Discounting
task (Dom et al., 2006). Assumptions with respect to the residuals
were checked and neuropsychological measures were logtransformed if necessary to achieve a normal distribution. Outliers
were dened as having a score more extreme than 4-times the
standard deviation above or below the mean per group. Details of
task and outcome measures are described in Supplementary
Table S1.
2.5. Statistical analysis
First, we performed a between-subject whole-skeleton voxel-wise
analysis using TBSS, in which we compared patients to control subjects
on values of FA, MD, AD, and RD. In all analyses, gender, age, and scan
acquisition protocol were included in the model as nuisance regressors.
Threshold-free cluster enhancement (TFCE) was applied to obtain
cluster-wise statistics corrected for multiple comparisons. Briey, this
method transforms local T-statistics into TFCE statistics that reect
both the size of the local effect (or height) and the cluster extent
(Smith and Nichols, 2009). With the obtained TFCE maps, randomize
then calculates a p-value (p-corrected) for each voxel, corrected for
whole-skeleton family-wise error (FWE) rate via permutation testing
(5000 permutations). The TFCE-corrected p-value maps were thresholded at PFWE = 0.05, and we report regions that contained clusters of
at least ten contiguous suprathreshold voxels. Signicant results were
localized to anatomical locations using the Johns Hopkins University
(JHU)ICBM-DTI-81 white matter labels atlas (Mori et al., 2008) and
the white matter tractography atlas (Hua et al., 2008). To estimate the
effect size of signicant clusters, spatially averaged scores were calculated from signicant clusters for each subject, and subsequently partial
eta-squared was calculated using SPSS version 21 (IBM, Chicago, IL).
Secondly, within the ADHD group we performed two wholeskeleton regression analyses in TBSS similar to van Ewijk et al. (2014).
This analysis was performed using self-reported symptom counts on
both dimensions (inattention and hyperactivity/impulsivity) as two
separate predictors. Gender, age, and scan acquisition protocol were included in the model as nuisance regressors. The TFCE-corrected p-value
maps were thresholded at PFWE = 0.05. In addition, two analyses were
performed in the ADHD group to further investigate signicant
between-group ndings from the rst TBSS analysis in an ROI approach
for their link with symptom severity. From each signicant FA and MD
cluster, an ROI mask was created and was then back-projected to the
original images of each individual; subsequently, spatially averaged FA
and MD values were obtained. Partial correlation analyses were performed (in SPSS) to identify correlations between the extracted average
of FA and MD for each cluster and self-reported symptom count on both
dimensions, adjusting for gender, age, and scan acquisition protocol.
Third, similar partial correlation analyses as listed above were
performed (in SPSS) for the extracted average of FA and MD (for each
cluster) and cognitive measures (working memory, attention, inhibition, delay discounting/impulsivity), adjusting for gender, age, and
scan acquisition protocol. These partial correlation analyses were performed in the whole group. Post-hoc analyses were carried out for signicant ndings, in which the ADHD and control group were tested
separately to explore potential group-specic effects. For the two latter
analyses, Bonferroni correction was used and the p-value of 0.05 was

17

divided by the number of signicant FA and MD clusters and multiplied

by two for the analysis with symptom dimensions and multiplied by
four for the analysis with the four cognitive measures.
Lastly, to explore whether stimulant medication or a history of
comorbid major depressive disorder, the most frequent comorbidity of
ADHD in our cohort, confounded our between-group results, general
linear models (GLM) were used (in SPSS). The extracted mean values
from the signicant between-group FA, MD, RD, and AD clusters were
included as dependent factors. For the GLM of medication, healthy
controls (N = 109), medication-naive patients (N = 20), and patients
using stimulant treatment (N = 64) were added as between subject
factors. For the GLM of depression history, healthy controls with no history of depressive episodes (N = 95), ADHD patients with no history of
depressive episodes (N = 43), and ADHD patients with one or more
episodes in the past (N = 52) were added as between subject factors.
Post-hoc analyses were performed using Fisher's least signicant difference (LSD).
3. Results
3.1. Demographic, clinical and cognitive measures
Across the two groups, there were no signicant differences in age of
participants or in gender distribution. As expected, patients with ADHD
scored signicantly higher on ADHD symptom counts and signicantly
worse on cognitive measures, compared to the control group. The details are summarized in Table 1.
3.2. Between-group TBSS analysis of white matter microstructure
The whole-skeleton voxel-based between-group analysis with TBSS
identied several clusters of decreased FA and increased MD and RD in
the ADHD group when compared to the control group (Table 2, Fig. 1).
No regions of increased FA or reduced MD or RD were observed, and no
differences were observed for AD. For FA, differences between patients
and controls were located in the body and splenium of the corpus
callosum, anterior and superior corona radiata, posterior thalamic radiation, and tapetum. For MD and RD, overlapping regions were found,
although casecontrol differences were even more widespread in both
right en left hemisphere, also encompassing internal and external
capsule, sagittal stratum, fornix, and SLF. The same pattern of results
was observed when the analysis for FA was limited to the single scan
acquisition protocol on which most scans were performed (N = 158;
Supplementary Table 4).
AD and RD are derived from three quantitative indices (i.e.
eigenvalues1, 2, 3) that index tissue structure based on water
molecule displacement. The rst eigenvalue (1) measures AD,
while RD is the average of the second (2) and third (3) eigenvalue.
As a consequence, the signal-to-noise ratio of RD is sqrt(2) (the
square root of 2) times higher than that of AD, which results in less
power (through higher standard errors) to detect AD differences
than RD differences. The absence of signicant AD clusters in conjunction with positive RD clusters in our sample might thus have
been due to power differences. In order to clarify this, we extracted
mean AD and RD with standard errors from the signicant
between-group FA clusters. As expected, we found that the standard
error for AD (3.14E 06) was 1.27 times higher than the one for RD
(2.46E 06). The mean RD values signicantly higher in the ADHD
group compared to controls, (F(1, 211) = 18.880, p = .00002),
while mean AD values were not (F(1, 211) = .739, p = .391). Furthermore, when we decomposed RD by extracting mean 2 and 3
from the signicant between-group FA clusters and compared
them between patients and controls, we found signicant differences between patients and controls for both 2 (F(1, 211) =
18.901, p = .00002) and 3 (F(1, 211) = 16.719, p = .00006).

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Table 2
Clusters showing signicant differences in Fractional Anisotropy (FA), Mean Diffusivity (MD), and Radial Diffusivity (RD) between ADHD patients (N = 107) and healthy
controls (N = 109).
Cluster

White matter tracts overlapping with the clusters

(size of overlap in N10 voxels)a

Size
(voxels)b

Clusters with signicantly lower FA in ADHD patients

1
Body and splenium of CC
2
Splenium of CC, SCR (R), PCR (R)
3
Body of CC, SCR (R)
4
Splenium of CC
5
PCR (R)
6
PTR (R), Tapetum (R)

453
141
140
56
32
16

Clusters with signicantly higher MD in ADHD patients

1
Body, splenium and genu of CC, EC (L + R), ACR (L + R), PCR (L + R), SCR (L), posterior
limb of IC (L + R), retrolenticular part of IC (L + R), anterior limb of IC (L), sagittal
stratum (R), cingulum, fornix (cres)/stria terminalis (L), CP (L), PTR (L + R), SFOF (L),
fornix (cres)/Stria terminalis (R)
2
SLF (L)
3
EC (L)
4
Sagittal stratum (L)
5
Sagittal stratum (L)
Clusters with signicantly higher RD in ADHD patients
1
Body, splenium and genu of CC, ACR (L + R), SCR (L + R), PCR (L + R), PTR (L + R), EC
(L), retrolenticular part of IC (L + R), anterior limb of IC (L), posterior limb of IC (L + R),
fornix (cres)/stria terminalis (L), sagittal stratum (L), SFOF (L), UF (L), SLF (L + R)
2
Sagittal stratum (R), EC (R), Fornix (cres)/Stria terminalis (R)
3
SLF (L)
4
SLF (L)

6763

407
40
36
16

8411

454
386
119

MNI coordinates
(x;y;z)

Partial
eta2c

pd

1;26;23
24;35;28
17;24;33
16;36;29
18;7;34
30;51;15

.080
.062
.068
.055
.048
.037

.042
.046
.040
.049
.049
.049

37;31;5

.153

.037

49;38;12
35;9;11
42;13;15
40;23;7

.126
.086
.076
.059

.042
.047
.048
.049

2;27;23

.133

.027

35;13;12
56;24;5
18;28;30

.099
.122
.049

.045
.044
.048

CC corpus callosum, ACR anterior corona radiata, FA fractional anisotropy, MD mean diffusivity, PCR posterior corona radiata, RD radial anisotropy, SCR superior corona radiata, RPIC
retrolenticular part of IC, PTR posterior thalamic radiation (include optic radiation), PLIC posterior limb of IC, SLF superior longitudinal fasciculus, IC internal capsule, EC external capsule,
SFOF superior fronto-occipital fasciculus, and UF uncinate fasciculus.
a
White matter tracts as dened with the Johns Hopkins University White Matter Label Atlas.
b
Cluster size N 10 voxels.
c
Partial eta squared based on mean FA, MD and RD of the cluster.
d
P b .05, FWE-corrected, controlling for gender, age and scan acquisition protocol.

3.3. Association test of FA and MD with symptom scores in patients with

ADHD

3.5. Effect of medication use and depression history on signicant betweensubject clusters of FA, MD, and RD

The whole-skeleton voxel-based regressions with TBSS in the

patients showed that both ADHD symptom domains (inattention and
hyperactivity/impulsivity) were not associated with FA or with MD.
Furthermore, the partial correlation analyses of mean values of the
signicant between-group FA and MD clusters with either symptom
domain did not show any signicant correlations (padj N .05).

Sensitivity analyses were conducted to examine possible effects of

stimulant medication use or depression history on signicant clusters
from the between-group analysis for FA, MD, and RD. Extracted mean
values from the signicant between-group clusters for FA, MD, and RD
did not differ between medication-naive and stimulant-treated patients
(p N .05) (Supplementary Table S2). There were no differences on the
extracted mean values between ADHD patients with no history of depressive episodes and ADHD patients with one or more episodes in
the past (p N .05) (Supplementary Table S3).

3.4. Association of FA and MD with cognitive measures in patients and

controls

4. Discussion
In the whole group, the partial correlation analyses showed that
inhibition performance was negatively correlated with FA in cluster
4 (r = .265; p = .0001), such that worse inhibition (i.e., more
commission errors on the SART) was linked to lower FA. The delay
discounting score was positively correlated with MD in cluster 1
(r = .242; p = .0008), such that steeper discounting on the Delay
Discounting task (i.e., higher impulsivity) was linked to higher MD.
To further explore which group contributed to the effects reported
above, post-hoc analyses in the patients and in the control group
separately revealed that the correlation with inhibition performance
was predominantly present in the control group (r = .288; p =
.004) and did not reach signicance in the ADHD patient group
(r = .179; p = .099). Steeper delay discounting was correlated
with MD only in the ADHD patient group (r = .283; p = .009) and
not among controls (r = .032; p = .750) (Fig. 2). There were no
signicant results for working memory or attentional performance
(Table 3).

In this study we examined white matter microstructure in adult

patients with ADHD and healthy controls. Compared to the healthy
individuals, patients with ADHD showed signicantly reduced FA and
increased MD and RD in several brain regions, but no differences in
AD. While FA and MD differences were not related with symptom severity, lower FA in the splenium of the corpus callosum was associated with
worse inhibition performance, and higher MD in several ROIs was associated with higher impulsivity.
Strongest effects were found in the body and splenium of the corpus
callosum. This supports earlier reports that white matter anomalies in
the corpus callosum are one of the most consistently found features in
childhood ADHD (Cao et al., 2010; Pavuluri et al., 2009; Qiu et al.,
2011; van Ewijk et al., 2014) and adult ADHD (Dramsdahl et al., 2012;
Konrad et al., 2010), although some studies did not nd corpus callosum
abnormalities (de Zeeuw et al., 2012; Hamilton et al., 2008; Hong et al.,
2014; Nagel et al., 2011; van Ewijk et al., 2012). Importantly, reduced FA

A.M.H. Onnink et al. / Progress in Neuro-Psychopharmacology & Biological Psychiatry 63 (2015) 1422

19

Fig. 1. Results from the tract-based spatial statistics (TBSS) analyses displayed on the MNI152 brain. Hot colors represent increased values, and cool colors represent decreased values.
Decreased fractional anisotropy (FA), increased mean diffusivity (MD) and radial diffusivity (RD) are shown in individuals with ADHD compared to controls (threshold-free cluster
enhancement, p b .05, corrected).

Fig. 2. Correlations between inhibition performance and mean FA in cluster 4 (a) and delay discounting score and mean MD in cluster 1 (b) for ADHD patients and controls separately;
*p b .05. Worse inhibition was reected by a higher number of commission errors as measured with the Sustained Attention to Response Task (SART) task, and higher impulsivity was
reected by steeper discounting in the Delay Discounting task.

20

A.M.H. Onnink et al. / Progress in Neuro-Psychopharmacology & Biological Psychiatry 63 (2015) 1422

Table 3
Partial correlations between mean Fractional Anisotropy (FA) and Mean Diffusivity (MD) of between-subject clusters and cognitive measures controlling for age, gender, and scan protocol.
Digit spana

FA cluster 1
FA cluster 2
FA cluster 3
FA cluster 4
FA cluster 5
FA cluster 6
MD cluster 1
MD cluster 2
MD cluster 3
MD cluster 4
MD cluster 5

SADb

SARTc

Delay discountingd

109 HC/103 ADHD (N)

106 HC/100 ADHD (N)

100 HC/90 ADHD (N)

102 HC/88 ADHD (N)

.136
.039
.066
.063
.1
.163

.105
.127
.090
.088
.054
.018
.201
.214

.223
.068
.036
.265
.101
.054
.160

.140
.051
.133
.213
.043
.175
.242

.054
.063
.108
.099
.033

.135
.144
.118

.072
.094
.071
.033

.121
.182
.142
.185

Indicates an uncorrected signicance of p b .05.

Indicates a corrected signicance of p b .001.
a
Digit Span raw backwards score (working memory).
b
Errors Sustained Attention Dots (SAD) task (attention).
c
Commission errors Sustained Attention to Response Task (SART) (inhibition).
d
Score on Delay Discounting task (impulsivity).

values in the splenium were associated with worse inhibition performance. Poorer response inhibition in healthy children has been correlated previously with decreased FA (and increased MD) in the splenium
(Paolozza et al., 2014). It has been linked to decreased splenium volume
in children prenatally exposed to polychlorinated biphenyls (Stewart
et al., 2003) and in adults with bipolar disorder (Bearden et al., 2011),
populations also characterized by insufcient inhibitory control. The
splenium of the corpus callosum connects interhemispheric somatosensory, auditory, occipital, and motor areas, which are important for visual
object recognition and discrimination. Possibly, commission errors arise
due to insufcient transmission of visual information to the brain areas
executing inhibitory control. Our results show that the association between splenium FA and inhibition performance was weaker in patients
than in healthy individuals, suggesting that this structure is less functional in ADHD patients.
Besides the corpus callosum, the observed differences in posterior
and superior regions of the corona radiata are consistent with ADHD
studies in childhood (Nagel et al., 2011; Qiu et al., 2011) and adulthood
(Cortese et al., 2013). These regions are continuations of the posterior
limb of the internal capsule to the sensorimotor cortex and contain
axons primarily involved in low-level motor function. Alterations in
these tracts might contribute to sensorimotor decits in adult ADHD
(Valera et al., 2010). Compared to controls, ADHD patients showed
reduced FA in the posterior thalamic radiation consistent with an earlier
nding in adult ADHD (Cortese et al., 2013), although a childhood study
showed increased rather than decreased FA in this area (Peterson et al.,
2011). The thalamic radiation contains bres that run towards the
occipital cortex carrying visual information and might be related to
structural visual cortex abnormalities (Ahrendts et al., 2011) and functional visual decits (Kim et al., 2014) in adult ADHD.
Our ndings of increased MD suggest that white matter cellular density is lower in ADHD patients (Alexander et al., 2007). In agreement
with earlier studies (de Luis-Garcia et al., 2015; Lawrence et al., 2013),
these ndings for MD were observed in more widespread areas of
the brain than those for FA and our nds support a recent study that increased MD was correlated with worse performance indicators of ADHD
(Conners Continuous Performance Test)(de Luis-Garcia et al., 2015).
Moreover, increased MD within a large cluster encompassing widespread regions was associated with steeper delay discounting. Steeper
delay discounting occurs when smaller immediate rewards are preferred over larger delayed rewards, and is linked to impulsivity. Earlier
studies found similarly that steeper delay discounting was associated
with higher MD (and lower FA) in bilateral frontal/temporal lobes and
in fronto-striatal tracts (Olson et al., 2009; Peper et al., 2013). A recent

resting-state functional connectivity study in childhood ADHD showed

that steeper delay discounting was related to differences in reward
circuit connectivity (Costa Dias et al., 2013). In conclusion, aberrant
structural and functional connectivity possibly inuences the balanced
interaction between the reward network and other cognitive control
regions. This may unveil vulnerability to impulsive decision making in
ADHD. Future research could benet from using a connectomics approach, combined with multimodal imaging that includes diffusion
measures as well as functional MRI (Hong et al., 2014; Shenton et al.,
2014).
Decreased FA found in ADHD patients was driven by increases in RD
rather than changes in AD. Although the biological correlates of those
measures are not yet entirely claried, it is believed that increases in
RD (with minimal changes in AD) reect decreased myelination, while
decreases in AD reect axonal damage or degeneration (Alexander
et al., 2007; Song et al., 2002). Whereas studies in young children and
adolescents with ADHD suggest delayed myelination (Nagel et al., 2011;
Tamm et al., 2012), our results support the only other adult ADHD
study that has investigated AD/RD and point to atypical myelination not
only being delayed but rather representing a persistent anomaly in
ADHD (Shaw et al., 2015). This implicates myelination as a novel target
for genomic studies and for more tailored pharmacological treatment
interventions.
We used two approaches to investigate effects of FA and MD on
symptom severity. The rst approach was a voxel-based regression
with TBSS adapted from van Ewijk et al. (2014). The second approach
was a conventional ROI analysis using the mean FA and MD of signicant between-group clusters as predictors for symptoms. Both approaches yielded non-signicant results, consistent with another adult
ADHD study showing no association between corpus callosum differences and symptom severity (Dramsdahl et al., 2012). While this suggests that white matter differences in adult ADHD are independent of
disease severity, a vast amount of literature does show relations with
severity (Ashtari et al., 2005; Nagel et al., 2011; Shang et al., 2013;
Shaw et al., 2015; van Ewijk et al., 2014). A rm conclusion on whether
this can be explained by differences based on e.g. the age of the sample
will have to await future analyses in larger samples. International
collaboration in consortia like the Enabling Neuro Imaging Genetics
through Meta-Analysis (ENIGMA) Consortium (www.ENIGMA.ini.usc.
edu), which runs a ADHD working group, might provide increased
power to clarify this point.
Our ndings did not differ between drug-nave ADHD patients and
stimulant medicated patients which supports prior studies that found
no confounding effects of (stimulant) medication (de Zeeuw et al.,

A.M.H. Onnink et al. / Progress in Neuro-Psychopharmacology & Biological Psychiatry 63 (2015) 1422

2012; Hamilton et al., 2008; van Ewijk et al., 2014). Additionally, our
ndings did not differ between ADHD patients with a history of major
depression and ADHD patients without this comorbidity. Since deviant
white matter integrity has also been found in numerous psychiatric disorders, it would be of particular interest to go across diagnostic boundaries in future studies and investigate whether certain white matter
abnormalities are specic for ADHD or are shared between disorders.
While our DTI study sample is the largest one published to date for
adult ADHD, it also has a limitation. We used two different diffusion
scan acquisition protocols. However, this could not have biased our results, as group representation did not differ across protocols, and
all analyses were performed with protocol as a covariate. Moreover,
the same pattern of results held up when the main between-subject
TBSS analysis for FA was limited to the single protocol on which most
scans were performed, albeit with lower signicance (PFWE = .10)
(see Supplementary Table S4). Additionally, we could not extensively
study the role of comorbid substance abuse, which is an important
concern considering the increased risk of substance use disorders in
patients with ADHD (Gorzkowska et al., 2014; Wilens, 2004). Adolescent substance use has harmful effects on the development of white
matter characteristics (Bava et al., 2013) and prefrontal cortex volume
(Lejuez et al., 2010). Importantly, microstructural damage in corpus
callosum has been suggested as a risk factor for alcohol use disorders
(De Bellis et al., 2008).
In conclusion, this study demonstrates white matter microstructure
alterations in adult ADHD and point to abnormal myelination. These
white matter changes might represent a core trait of persistent ADHD
that is independent of disease severity. The white matter microstructure
alterations may have specic functional relevance given that lower FA in
the corpus callosum was related to inhibition problems and increased
MD in wide-spread tracts was related to impulsive decision making.
Conict of interests
Cornelis C. Kan was a paid member of the European Adult ADHD
Advisory Board of Eli Lilly in 2011 and 2012. Jan Buitelaar has served
as a consultant, advisory board member, or speaker for Bristol-Myers
Squibb, Janssen Cilag BV, Eli Lilly, Novartis, Schering-Plough, Shire,
Servier, and UCB. He is not a stock shareholder of any of these companies. He has no other nancial or material support, including expert testimony, patents, and royalties. Barbara Franke has received a speaker fee
from Merz. The other authors report no nancial relationships with
commercial interests.
Acknowledgements
The authors thank Paul Gaalman for technical assistance with MRI
scanning. The authors also thank all of the participants of this study.
We would also like to thank the anonymous reviewers for their valuable
comments. This study was supported by a grant from the Brain & Cognition Excellence Program and a Vici grant (to BF) of the Netherlands
Organization for Scientic Research (NWO, grant numbers 433-09229 and 016-130-669) and in part by the Netherlands Brain Foundation
(grant number, 15F07[2]27). The research leading to these results also
received funding from the European Community's Seventh Framework
Programme (FP7/20072013) under grant agreement no. 602805
(Aggressotype) and no. 602450 (IMAGEMEND). In addition, the research received funding from the National Institutes of Health (NIH)
Consortium grant U54 EB020403, supported by a cross-NIH alliance
that funds Big Data to Knowledge Centers of Excellence (BD2K).
Appendix A. Supplementary data
Supplementary data to this article can be found online at http://dx.
doi.org/10.1016/j.pnpbp.2015.04.008.

21

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